Catalytic Immunity and Autoimmune Mechanisms

  • Tramontano, Alfonso (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Antibodies and their fragments that specifically break down proteins and peptides are found in an autoimmune context, in multiple myeloma and in certain experimental immune responses elicited against viral polypeptides. Studies support the premise that antibodies with catalytic activity are inherent to the immune repertoire, but may be excluded from dominant responses in the healthy immune subject. Two approaches are described that could lead to production of efficient serine protease-like catalytic antibodies. A new method of immunization is proposed to specifically elicit antibodies that utilize covalent reactivity in antigen binding. Antibodies induced in the covalent immunization procedure will be characterized for hydrolytic activity against defined peptide analogs. Differences in the covalent immunization responses in normal and autoimmune mice will be investigated to reveal possible mechanisms of its regulation. Alternatively, covalent binding will be used to select recombinant antibodies represented on phage display libraries. The recombinant clones or hybridomas from immunized mice will be screened for expression of monoclonal antibodies with covalent binding and efficient peptidase activities. The primary sequence, specificity and kinetic efficiency of defined clones will be studied to identify molecular and functional attributes of the efficient catalysts. These methods will be applied to develop specific proteolytic antibodies against the cytokine TNF-alpha. Potential involvement of catalytic antibodies that cleave TNF-alpha in regulating immune responses and cytotoxicity will be examined. Antibodies that efficiently degrade self or foreign antigens could provide a direct mechanism for neutralization and thus significantly enhance the immune system's capacity to mount protective responses against cancer, chronic inflammation or infectious agents. These efforts could lead to useful applications as therapeutics or for enhanced vaccine design.
StatusFinished
Effective start/end date4/1/023/31/07

Funding

  • National Institutes of Health: $210,119.00
  • National Institutes of Health: $264,330.00
  • National Institutes of Health: $264,330.00
  • National Institutes of Health: $55,472.00

ASJC

  • Medicine(all)

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